CN110461321A - Composition containing N- acetyl diaminobutyric acid - Google Patents

Composition containing N- acetyl diaminobutyric acid Download PDF

Info

Publication number
CN110461321A
CN110461321A CN201780087060.3A CN201780087060A CN110461321A CN 110461321 A CN110461321 A CN 110461321A CN 201780087060 A CN201780087060 A CN 201780087060A CN 110461321 A CN110461321 A CN 110461321A
Authority
CN
China
Prior art keywords
diaminobutyric acid
acetyl
composition
salt
ester
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN201780087060.3A
Other languages
Chinese (zh)
Inventor
A·比尔施泰因
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bitop AG
Original Assignee
Bitop AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Bitop AG filed Critical Bitop AG
Publication of CN110461321A publication Critical patent/CN110461321A/en
Pending legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N1/00—Preservation of bodies of humans or animals, or parts thereof
    • A01N1/02—Preservation of living parts
    • A01N1/0205—Chemical aspects
    • A01N1/021—Preservation or perfusion media, liquids, solids or gases used in the preservation of cells, tissue, organs or bodily fluids
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N1/00—Preservation of bodies of humans or animals, or parts thereof
    • A01N1/02—Preservation of living parts
    • A01N1/0205—Chemical aspects
    • A01N1/021—Preservation or perfusion media, liquids, solids or gases used in the preservation of cells, tissue, organs or bodily fluids
    • A01N1/0226—Physiologically active agents, i.e. substances affecting physiological processes of cells and tissue to be preserved, e.g. anti-oxidants or nutrients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/40—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
    • A61K8/44—Aminocarboxylic acids or derivatives thereof, e.g. aminocarboxylic acids containing sulfur; Salts; Esters or N-acylated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/04—Antipruritics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q17/00—Barrier preparations; Preparations brought into direct contact with the skin for affording protection against external influences, e.g. sunlight, X-rays or other harmful rays, corrosive materials, bacteria or insect stings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q17/00—Barrier preparations; Preparations brought into direct contact with the skin for affording protection against external influences, e.g. sunlight, X-rays or other harmful rays, corrosive materials, bacteria or insect stings
    • A61Q17/04—Topical preparations for affording protection against sunlight or other radiation; Topical sun tanning preparations
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/007—Preparations for dry skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/08—Anti-ageing preparations

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Dermatology (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Zoology (AREA)
  • Environmental Sciences (AREA)
  • Wood Science & Technology (AREA)
  • Dentistry (AREA)
  • Birds (AREA)
  • Physiology (AREA)
  • Biophysics (AREA)
  • Gerontology & Geriatric Medicine (AREA)
  • Pulmonology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Agricultural Chemicals And Associated Chemicals (AREA)

Abstract

The present invention relates to contain N- acetyl diaminobutyric acid, the application of the salt of N- acetyl diaminobutyric acid or the composition of ester in the method for the treatment of human body or animal body.

Description

Composition containing N- acetyl diaminobutyric acid
The present invention relates to contain N- acetyl diaminobutyric acid, the salt of the compound or the composition of ester.
Ectoin (Ectoine) (2- methyl-1,4,5,6- tetrahydropyrimidine -4- carboxylic acid) and hydroxyl-Ectoin (5- hydroxyl Base -2- methyl-1,4,5,6- tetrahydropyrimidine -4- carboxylic acids) it is the In in extreme compatibility microorganism, particularly halophilic microorganism The compatible solute synthesized under stressed condition.It is heretofore described the various applications of Ectoin and hydroxyl Ectoin Or purposes, such as moisturizer, for treating vascular leak syndrome (VLS) (10 2,006 056 766 A1 of DE) or using In treatment neurodermatitis (103 30 243 A1 of DE).
Ectoin can be with chemical synthesis (referring to WO2010/006792A1), but is mainly thin by the thermophilic salt that continuously ferments Then bacterium Halomonas elongata passes through " bacterial milking " and obtains Ectoin.In this process, the environment item of bacterium Part sudden change, then the Ectoin of generation is discharged into environment by they.
Biosynthesis is since aspartic semialdehyde.Initially, it is catalyzed and is generated by transaminase 2,4-diaminobutyric acid.It should Acid forms N- γ-acetyl group-L-2,4- diaminobutyric acid (NADA) by transacetylase acetylation.It is inside contracted finally, carrying out molecule Reaction is closed to form Ectoin, which synthesizes enzymatic by Ectoin.
Therefore, as the intermediate stage, N- γ-acetyl group -2,4-diamino-butanoic or N- γ-acetyl group -2,4- be experienced The substances such as diaminobutyric acid ester.So far, which is not considered especially important, but surprisingly, it has been found that N- Acetyl diaminobutyric acid can generate physiological effect and can be used for the treatment of human body or animal body, at prevention and beauty Reason.So far, this effect of N- acetyl diaminobutyric acid is unknown.Although Canovas et al., Appl.ENVIRON.Microbiol.1999；65 (9): 3774-3779 describes N- γ-acetyl group -2,4- diaminobutyric acid and exists Effect in terms of enzyme stabilization, they do not provide and illustrate treatment use.Therefore, N- acetyl diaminobutyric acid can be used as Drug, drug, curable product simultaneously can be used as cosmetics.
As described above, N- acetyl diaminobutyric acid is the intermediate stage for generating Ectoin, but buck can also be passed through It solves and is readily available in commercially available Ectoin.For example, Ectoin can be reacted with 2M KOH solution to obtain About 80%N- γ-acetyl group-L-2,4- diaminobutyric acid ((2S) -4- acetylaminohydroxyphenylarsonic acid 2-amino-butyric acid) and about 20%N- α-second Acyl group-L-2,4- diaminobutyric acid ((2S) -2- acetylaminohydroxyphenylarsonic acid 4-Aminobutanoicacid).Two kinds of isomers, i.e. γ-and alpha-isomer, Have proved to be physiologically effective.
The use of shown stereoisomer, that is, L- or S- enantiomer is preferred but is not enforceable, it means that can also To use D- or R- enantiomer or racemate.
In general, other than N- acetyl diaminobutyric acid, can also use relevant derivative, especially salt or Ester.About relevant ester derivant, the COOH group of N- acetyl diaminobutyric acid is replaced by carboxylate function COOR, wherein R represents saturations or undersaturated straight chain or branched alkyl, naphthenic base, aryl, heteroaryl, alkylaryl, aryl alkyl, alkoxy Alkyl, alkylthio alkyl, aryloxy alkyl or arylthio alkyl.Particularly, it can be C1,C2,C3,C4,C5,C6,C7,C8, C9,C10,C11,C12,C13,C14,C15,C16,C17Or C18Alkyl.Each ester can also exist with ion or zwitterionic form, that is, The present invention includes the salt using the ester.Pharmacologically acceptable salt includes, for example, alkali metal, alkaline-earth metal and ammonium salt, especially It is potassium, sodium, magnesium and calcium salt.
In the context of the present patent application, N- acetyl diaminobutyric acid or NADA are usually referred to, but regardless of described point Which functional group of son is protonated or with charge.In fact, due to existing simultaneously carboxyl and amido functional group, the molecule Exist usually in the form of zwitterionic.
It has been found that N- acetyl diaminobutyric acid can be obviously improved the barrier function of epithelium.Except connective tissue, muscle Outside tissue and nerve fiber, epithelium is one of existing four kinds of major tissue types in human body.It is made of epithelial cell, epithelium Cell largely seamlessly links together and is arranged in one or more layers.Particularly, epithelial tissue is for protecting With the surface of limitation body (skin) and the internal layer of organ, blood vessel etc..Other than its defencive function, epithelium is also realized such as to be inhaled again The function of receiving and secrete.Epithelium is separated by basilar memebrane with following connective tissue.
A variety of diseases are related with epithelial barrier dysfunction, therefore reinforcement barrier function can prevent undesirable external shadow It rings.Once these undesirable external actions overcome epithelial barrier, they usually have Trigger Function, lead to inflammatory cascade.Cause This, N- acetyl diaminobutyric acid or derivatives thereof is effectively applied to many treatment human bodies or animal body to the stabilisation of barrier Method in.
N- acetyl diaminobutyric acid is apparently based on the molecule with lyophily effect to the stabilization of barrier, that is, promotes The fact that hydrogen bond formation.As a result, also promoting the biomolecule of native form, such as protein.On the other hand, N- acetyl group two Aminobutyric acid is excluded except the hydration shell of biomolecule；Lipid film becomes more mobility.Therefore, film and protein all may be used To resist most diverse influence.The integrality of disturbed tissue engagement structure and membrane structure is restored.
Another effect of N- acetyl diaminobutyric acid is the up-regulation of tight junction protein (claudin).These are to make For the memebrane protein of close-connected a part, closes the narrowband of epithelial cell and be connected to the band of flanking cell.Epithelium it is thin The forfeiture in space produces barrier between born of the same parents, and the entrance of molecule is controlled by epithelium.In addition to closed protein, hole occlusive is tight The up-regulation of close connection albumen plays most important effect as memebrane protein, so that the density of epithelial membrane increases, and leads to permeability It reduces.
This patent disclosure relates generally to the treatments and cosmetic applications of N- acetyl diaminobutyric acid and its derivative.
Treatment dry skin and mucous membrane are dry
According to preferred embodiment, the composition containing N- acetyl diaminobutyric acid is for treating and/or preventing skin In the method that skin is dry or mucous membrane is dry.Wetting property is confirmed using the measurement based on SIRC cell line.Specifically, N- acetyl Base diaminobutyric acid is in skin, stimulated skin and the flaky skin (flaky skin) to dry skin, very dry Processing in have nursing role.In addition, N- acetyl diaminobutyric acid can also be used for the dry inflammation skin for the treatment of, for example, In the case where atopic dermatitis (neurodermatitis).
Composition of the present invention is suitable for maintaining and restoring the normal moisture content of skin.The content is usually by skin Skin itself is adjusted, but this self-regulating function may be inherent by dry environment air etc. or external action is done It disturbs.As a result, the flaky skin and small gap that are formed in skin increase, keep skin more sensitive to other influences.N- acetyl group diamino Base butyric acid can be in conjunction with the moisture in skin, to increase the moisture content of skin.The skin that the present invention defines further includes hairiness The skin of hair, especially scalp.Moreover, can treat or prevent inherent skin aging by means of composition provided by the invention Phenomenon.These should be understood that the sign of skin aging, the sign are not the total spokes of external action such as ultraviolet radiation or the sun The result penetrated.
As described above, composition proposed by the present invention can also be used for treatment atopic dermatitis (neurodermatitis).This is one Kind chronic dermatosis, cannot cure completely, and feature is serious itch etc..Usually to this to scratch response, this will lead to patient Additional skin irritatin.Skin is characterized in that special dry and strong inflammation tendency, causes to form red squama on skin Shape eczema.The background of atopic dermatitis is not fully understood；Heredity and the influence of immune factor and environment may all work.It should Childhood that disease frequently occurs in and about 1% to 3% adult in.
Up to the present, the treatment of atopic dermatitis is mainly symptomatic treatment.Particularly, it can be used with moisture-keeping functions Active material, such as panthenol or dexpanthenol also have anti-inflammatory and antipruritic characteristic.In addition to this, commonly using sugared cortex Hormone also has anti-inflammatory effect, but also related with side effect such as atrophy (thinning of skin).
In contrast, any side effect is unlikely to cause using N- acetyl diaminobutyric acid or have significantly less Side effect.It can also combine the composition of N- acetyl diaminobutyric acid with other active components, such as above-mentioned active constituent (dextrorotation) panthenol or glucocorticoid.Anti-inflammatory agent and antibiotic, restraining epiphyte or mycocide are usually also used in this context Object, antibiotic or the substance and antalgesic for mitigating itch.
In addition, N- acetyl diaminobutyric acid can also be used for treatment mucous membrane drying.It is particularly importantly viscous to dry nose The treatment of film, oral mucosa, eye mucosa and vagina mucosa (vagina epithelium).Other than smell, nose can also complete other Vital task: breathing air is cleaned, the air of sucking is heated to body temperature and is humidified by removal little particle.In this way It eliminates virulence factor and most advantageously prepares the gas exchanges in lung.However, only when schneiderian membrane can sufficiently humidify breathing When air, this could be worked normally.If air is special dry, when winter or the air humidity of air-conditioned room is likely lower than and often stands 5 grams of water of square rice air, then the ability of schneiderian membrane will soon prove deficiency.In this case, it is possible to will appear drying property nose Symptoms such as scorching (dry nose diseases), while with itch, burning heat sensation and crust to be formed at eczema.It there may come a time when that nosebleed can occur, i.e., Make not catch a cold, also can usually block nasal passage.Importantly, over-drying, supercooling and filtered air are sooner or later Pathogenic organisms can be carried and enter respiratory tract.
A kind of performance of " dry nose syndrome " is rhinitis sicca and another kind is atrophic rhinitis, it is also possible to nose Certain drug therapy and side effect that is long-term or resting on air-conditioned room repeatedly.In addition, many patients with schneiderian membrane are Heavy smoker.
It is typically chosen the drug dry as treatment nose using aqueous isotonic salt solution.However, with Sprayable The treatment of application medicament may not always generate satisfactory effect and must often repeat.With other nasal formulations phases Than the preparation of viscosity higher provides peculiar advantage: compared with aqueous nasal drop or spray, they are protected on schneiderian membrane Hold the longer time.Therefore, nursing efficacy is stronger.However, giving aqueous adhesive formulation, there are one disadvantages, i.e., in viscosity increasing agent In water evaporation after can generate undesirable scab.In addition, the side effect of most serious or problem are printed with the subjective of " nose is dry " As related, can be used for treating such case almost without any obvious satisfactory treatment at present.Had using adhesive formulation scarce Point, because their usual arrival vestibulum nasis cause the treatment of schneiderian membrane upper zone insufficient.Vessel retraction or schneiderian membrane subtract The repeated application of congested agent addition agent (sympathomimetic nerve domination object) frequently results in schneiderian membrane drying, this may cause inflammation thorn Swash.These side effects may bring main infection risk, because the mucous membrane under dry and inflammatory status will no longer be able to enable People satisfactorily executes its protection and filtering function, so that pathogenic organisms may enter anatomy air flue unblockedly.
However, composition proposed by the present invention is very suitable for the dry prevention of schneiderian membrane, treatment and/or nursing, and The shortcomings that avoiding the prior art as described above.In addition, the composition can contain sodium chloride or other moisturizer, such as hard Portugal Glycan.Especially for salt composite is contained, select method for thickening meaningful, it is pharyngeal to prevent preparation from entering as far as possible.
In addition, synergistic effect also may be implemented by the way that N- acetyl diaminobutyric acid and other active materials is given in combination. For example, the congestion effect of oxymetazoline, Xylometazoline (xylometazoline) or Tramazoline (tramazoline) can be with It is combined with the effect of N- acetyl diaminobutyric acid.Specifically, which can be with other substances such as dexpanthenol or panthenol Anti-inflammatory effect combine.Another achievable combination may be implemented with antihistamine such as azelastine or Cromoglycic acid.May be used also To use the substance such as hydroxypropyl methyl cellulose for increasing viscosity, hyetellose (hyetellose), hydroxypropyl methyl fiber Plain (hypromellose) or hyaluronic acid carry out other combinations with wetting substances such as sesame oil.
However, the composition treatment mucous membrane of theme is not limited to the dry treatment of schneiderian membrane through the invention；Other mucous membranes It can effectively be soaked with N- acetyl diaminobutyric acid.Its application is especially important for the mucous membrane of oral cavity and eyes.Dry (xerostomia) may have different reasons, especially with the common adverse effect of drug therapy.Oral mucosa drying causes Dysphagia and speech problems.In addition, decayed tooth is recurrent consequence, because the salivary flow that can be taken care of one's teeth is by obvious It hinders.
The drying of the oral mucosa as caused by treatment of cancer especially frequently encounters, either as cell inhibit therapy or It is the result of radiotherapy.Background herein is that the cell with high division rate, the cell are specifically attacked in treatment of cancer It further include mucomembranous cell in addition to cancer cell.
The mucous membrane (conjunctiva) of eyes may also be influenced by drying, dry to be also referred to as dry eye syndrome or drying property angle Conjunctivitis.Symptom related to this is foreign body sensation, and eyes are scorching hot and red and swollen.In severe cases, it may occur that cornea damage Wound is even blinded.Keratoconjunctivitis sicca is a kind of common disease, and there are about 10% to 20% adults to suffer from this disease.It is logical Hyaluronic acid, artificial tears or cellulose derivative are often used to provide treatment.However, since success rate is lower or secondary make occurs With this treatment is unsatisfactory.Another form of dry eyes are xerophthalmia (xerophthalmia), usually influence children, It is mainly seen in developing country.N- acetyl diaminobutyric acid or related derivatives can be used or use and contain N- acetyl group two The composition of aminobutyric acid treats the dry mucous membranes of eyes.In addition, the composition can contain other active constituents, such as transparent Matter acid is also used for treatment keratoconjunctivitis sicca.
Another application field is that vagina is wet, i.e. the humidifying of vagina mucosa.In general, postmenopausal women is dry with vagina Dry, the colpoxerosis is related with estrogen deficiency and vagina epithelium retrogression.However, young woman may also be by shadow It rings.
Protect skin or mucous membrane from external action
According to another preferred embodiment, used containing the composition of N- acetyl diaminobutyric acid or respective derivative In being intended to protect human skin or mucous membrane from physics, in the method for chemistry and/or biotic influence.Particularly, this may relate to Radiation, especially UV (ultraviolet light) or (infrared) radiation of IR, but also include such as visible light.
The skin disruption effect of commonly known UV radiation.In addition to the short-term erythemal effect that sunburn progress becomes, in the present invention In it should also be mentioned that damage to DNA, in the long run, this, which may cause, develops into cancer, especially melanoma.In addition, purple UV radiation can also destroy collagen and cause premature skin ageing.Conventional sunscreen agent or pass through object as titanium dioxide Reason effect and the illumination on reflexes Skin or the organic molecule by means of including in sun-screening agent are absorbed by chemical action broken UV light in bad property wave-length coverage.
However, concern of the IR radiation in public cognitive is less, it is also possible to cause lasting damage to skin.This is because It may cause the temperature effect of cell protein denaturation.
It can also be protected for further external action by N- acetyl diaminobutyric acid.Specifically, chemical It include anaphylactogen with biotic influence, heat, irritation or oxidisability or denaturation substance, suspended particulate matter and free radical.For example, logical It crosses and is exposed to ultraviolet radiation, ionising radiation, smoke from cigarette or ozone generate free radicals.As to certain present in environment The effect again of substance such as insecticide, herbicide or food composition, can also promote the formation of free radical.This is equally applicable to The pressure that a large amount of crowds are faced.Free radical can destroy the membrane tissue of body, to facilitate the development of disease.Free radical is also It can accelerate the evidence for senescence such as aging course and skin aging.Specifically, skin dehydration, skin can be prevented for the protection of free radical Skin disease and senile plaque.
It has been determined that N- acetyl diaminobutyric acid can stablize the cell membrane of keratinocyte to resist UV radiation.Also It was demonstrated that N- acetyl diaminobutyric acid can protect cells from IR radiation, the influence of visible light and heat.Similarly, it provides For other physics, the protection of chemistry or biotic influence in particular for anaphylactogen, has irritation or oxidation or denaturation Substance and free radical.In addition, the influence of suspended particulate substance confrontation skin is the result of physical influence.Especially average grain diameter≤ 15 μm, suspended particulate matter (also referred to as fine dust) especially≤10 μm may cause skin aging symptom.This suspension Grain is usually generated by the burning of fossil fuel, but also with sand, spore, pollen, rock powder, agricultural, mining, tobacco consumption, wheel Tire abrasion, the form of brake wear or the result as forest fire occur.
Other skin diseases can also use N- acetyl diaminobutyric acid or related derivatives prevention or treatment.Except above-mentioned disease Outside, this kind of disease includes psoriasis, seborrheic eczema, rosacea, nettle rash (nettle rash), actinic keratoma, skin disease (such as photodermatosis (light dermatosis)), contact eczema (such as Allergic Contact eczema), various shapes The moss (lichen) of formula, ichthyosis, diaper dermatitis, diaper rash.Can also drug treatment to for example fight rubefaction, swell It is swollen, blistering, rubeola, exfoliating skin and patch.Composition containing N- acetyl diaminobutyric acid or corresponding derivative also can be used In treatment disease, the specifically inflammation of mouth or larynx mucous membrane.
In terms of the treatment of scalp also can handle or be related to inside, therefore it can treat not directly as caused by external action Scalp problems.It is very common that scalp is reduced by hair growth and hair is graying is influenced.The case where hair growth is reduced Under, the balance between hair growth and alopecia, which is interfered, leads to long-term alopecia and bald, and this phenomenon is with androgenetic The form of baldness ratio in male more frequently occurs in women.The reason of hereditary alopecia is that hair follicle surpasses dihydrotestosterone Sensibility, this causes the growth period of hair to be obviously shortened.In addition, there are also inflammatory hair loss disorders.On the other hand, hair is ashed substantially Similarly influence male and female.
Lacking melanin production in hair follicle causes trichochromes to decline.Then, non-pigmented hair optically seems As white, or achromachia is mixed into the hair still coloured.Melanin can be prevented by being handled with N- acetyl diaminobutyric acid The damage of generation, therefore help to maintain the natural colour of hair.
The treatment of respiratory disease
Another aspect of the present invention relates to the compositions containing N- acetyl diaminobutyric acid or corresponding derivative, are used for In the method for the treatment of and/or prevention respiratory disease.These include the respiratory disease as caused by the influence of suspended particulates, special It is not pulmonary disease.
Especially in metropolis, people are exposed to a large amount of suspended particulate matter in air, these particulate matters come from Various sources, such as the exhaust gas of diesel vehicle, tobacco consumption, pollen, fungal spore, agricultural, petroleum and timber heating system, hair Power station, especially with the inhalable particles substance of particle diameter < 10 μm, the especially inhalable particles of particle diameter < 2.5 μm Substance.This particle extremely fine cannot by nasopharynx mucous membrane film and hair be sufficiently reserved.In general, particle is smaller, they can More to go deep into lung.For example, < 2.5 μm of particle can be penetrated into alveolar and only very slowly be eliminated therefrom.
Disease caused by effect by suspended particulate matter can be for example including allergy, bronchial asthma, and lung cancer is chronic Bronchitis, COPD (chronic obstructive pulmonary disease), silicosis or pulmonary fibrosis.COPD specifically includes pulmonary emphysema and chronic obstructive Bronchitis.
It is not due to the influence of suspended particulate but the respiratory disease as caused by allergy or virus infection can also use N- second Acyl group diaminobutyric acid and related derivatives treatment.These diseases include allergic rhinitis, asthma, common cold, acute rhinitis (flu), acute or chronic bronchitis, influenza and pneumonia.
Respiratory disease usually has viral pathogen.In general, they are as caused by rhinovirus and adenovirus.Rhinovirus sense Schneiderian membrane and larynx mucous membrane are contaminated, leads to acute rhinitis (head flu), less sees acute bronchitis.Human body passes through schneiderian membrane Inflammatory reaction makes a response to virus outburst.The blood vessel of mucous membrane becomes more permeability and secretes increase.Schneiderian membrane passes through nose Son expands and hinders/hinder to breathe.Furthermore, it is possible to occur not accommodate headache.In addition to virus infection, the secondary infection of bacterium is usual Occur in throat and pharyngeal.
The range of the respiratory disease as caused by adenovirus is from simple flu to bronchitis even pneumonia.Immune system Weaker patient is particularly susceptible to the influence of severe complication caused by adenovirus infection, such as ARDS (acute respiratory distress Syndrome).
In recent decades, allergic respiratory sharply increases, especially in industrialized country.Allergic rhinitis may Caused due to different anaphylactogens, such as pollen or house dust.This disease is based on inflammation, is finally raw Defensive reaction of the object to stimulation caused by anaphylactogen.By the effect of anaphylactogen, inflammatory Jie is discharged by t helper cell Matter, especially histamine and interleukin 8, leukotriene and tumor necrosis factor-alpha (TNF-α) activate internal inflammation control The downstream of system cascades.Anaphylactogen exposure progress during, by external action act on epithelial cell adhesion molecule also by It influences, the molecule is more or less generated.For example, exposure stress lead to table of the ICAM-1 molecule in impacted cell Up to stronger.
The anaphylactogen breathed in air causes respiratory response, generally entails myxedema and hypersecretion (allergia nose Inflammation, hay fever) and bronchial asthma.In the case where the exposure of extra high anaphylactogen, it may occur however that direct general reaction, This may cause anaphylactic shock in some cases.
In addition, N- acetyl diaminobutyric acid can also cure, mitigate or prevent the other diseases as caused by anaphylactogen.Tool Body includes allergic conjunctivitis.Anaphylactogen in surrounding air often cause respiratory tract, particularly nose and eye not It is suitable.In this case, anaphylactic hypersensitivity leads to itch, rubescent and increase of shedding tears.Other inflammation of conjunctivitis, commonly referred to as For conjunctivitis, it is also possible to which N- acetyl diaminobutyric acid prevents and treats, regardless of whether conjunctivitis has bacterium, virus, machinery Reason or as caused by fungi, helminth or laser therapy.Conjunctiva is mucous membrane；N- acetyl diaminobutyric acid is protected on conjunctiva Skin is from external action.
In general, the composition containing one of N- acetyl diaminobutyric acid or the derivative can be used for treating breathing Systemic disease, no matter these are anaphylaxis or viral, are all the effects due to suspended particulate or have an other reasons.This Outside, lung's senile symptom of such as senile emphysema can also be treated.These diseases may will affect the different parts of respiratory tract, Such as lung, nose and larynx.It can include allergic rhinitis, anaphylaxis or non-with the respiratory disease that N- acetyl diaminobutyric acid is treated Allergic bronchial asthma, bronchial hyperresponsiveness, common cold, acute rhinitis, acute or chronic bronchitis are popular sexy It emits, pneumonia, COPD, chronic obstructive bronchitis, pulmonary emphysema, lung cancer, ARDS (acute respiratory distress syndrome), capsule fiber Change, pulmonary fibrosis, silicosis and sarcoidosis.
Particularly, composition can be provided in inhalable form.Therefore, it can exist in the form of liquid or solid, Wherein composition is atomized into aerosol by means of the suction apparatus provided for this purpose and is sucked by patient.Usual use can be used In the conventional additives of preparation inhalable composition.Particularly, N- acetyl diaminobutyric acid can reside in water.It can be with It is envisioned that antasthmatic is added into composition, bronchus lytic agent or expectorant.
In general, composition according to the present invention passes through respiratory tract administration, especially nose administration, to antiallergy or virus The respiratory disease of induction.Administration is particularly preferred in the form of nasal spray or nasal drop.N- acetyl diaminobutyric acid Epithelial cell and nose during allergic rhinitis (Hay Fever) common inflammatory reaction are attributed to the effect of allergic rhinitis The interaction of related allergen (such as pollen) leads to the up-regulation of adhesion molecule such as ICAM-1 in these cells in epithelial cell, This is that flu the prerequisite of clinical symptoms occurs.Inventor observes, passes through the proinflammatory stimulation of N- acetyl diaminobutyric acid It can inhibit the up-regulation of ICAM-1.
ICAM-1 molecule serves not only as the adhesion molecule of other cells, the also receptor as rhinovirus described above.This Outside, rhinovirus infection causes the expression of ICAM-1 in airway epithelial cell to increase.In this respect, penetrant treating can prevent Or weaken the up-regulation of ICAM-1 molecule in nasal epithelial cells, to prevent the expression of this rhinovirus receptor, so as to prevent Or weaken rhinovirus infection man-based development and generation.There are CAR receptors in the adhesion complex of cell, are used as adenovirus Docking site.Then the different serotypes of Adenoviridae utilize different other receptor (integrin, CD46, acetyl sulfate livers Plain glycosaminoglycan, CD80, CD86 and MHC-1 member) intrusion cell.Therefore, it is handled by penetrant to adhesion molecule expression Modification can also weaken or may prevent adenovirus docking (dock) or penetrate into the ability of cell.
N- acetyl diaminobutyric acid can be administered together with other active materials, such as solid with antihistamine or cortex class Alcohol is specifically that glucocorticoid is administered together.Have shown that their side effect can be reduced in this case.Work as active matter When matter is not applied in single composition, also it is contemplated that being administered in combination, wherein close coordination is applied in time each other, so that living Property substance can functionally interact.In this respect, the invention further relates to kit, one of composition contains N- Acetyl diaminobutyric acid, another composition contain at least one antihistamine and/or at least one corticosteroid.
Can be used corticosteroid, be specifically glucocorticoid, as dexamethasone (dexamethasone), cloth how Moral (budesonide), betamethasone (betamethasone), triamcinolone (triamcinolone), fluocortolone (fluocortolone), methylprednisolone (methylprednisolone), deflazacort (deflazacort), prednisolone (prednisolone), prednisone (prednisone), Cloprednol (cloprednole), cortisone (cortisone), hydrogen Change cortisone (hydrocortisone), Fluocortin (fluocortine), clocortolone (clocortolone), clobetasone (clobetasone), alclometasone (alclomethasone), flumethasone (flumethasone), Fluprednidene (fluoprednidene), fludroxycortide (fluorandrenolone), prednicarbate (prednicarbate), Mometasone (mometasone), methylprednisolone, fluticasone (fluticasone), tooth rice pine (halometasone), fluocinolone acetonide (fluocinolone), diflorasone (diflorasone), remove light meter Song (desoximetasone), Fluocinonide (fluocinonide), fludrocortison (fludrocortisone), deflazacort, Rimexolone (rimexolone), chlorine sprinkle Buddhist nun's alcohol, Amcinonide (amcinonide), Halcinonide (halcinonide), double fluocortolones (diflucortolone), chlorine times Salt, ester, amide, solvate or the hydrate of his rope (clobetasol) or these compounds.
Another advantageous combination is N- acetyl diaminobutyric acid and GM-CSF, leukotriene such as LTB4, theophylline (1,3- bis- Methyl xanthine), leukotriene antagonist, phosphodiesterase inhibitors (PDE inhibitor, especially PDE4 inhibitor), muscarine Receptor antagonist, anticholinergic drug such as Ipratropium Bromide or Tiotropium Bromide or other active pharmaceutical ingredients.
Treat gastrointestinal tract chronic inflammation disease
The another application field of composition of the invention comprising N- acetyl diaminobutyric acid or related derivatives is to control Treat or prevent gastrointestinal tract chronic inflammatory disease, specifically Crohn disease, ulcerative colitis and gastritis.Crohn disease and exedens Colitis is the chronic inflammation of intestinal mucosa.In the application, N- acetyl diaminobutyric acid is thus it is shown that its is anti-inflammatory latent Power, the substance specifically act on enterocyte.N- acetyl diaminobutyric acid can also be used for the other diseases for the treatment of gastrointestinal tract, Such as the inflammation of gastric mucosa (gastritis) or irritable bowel syndrome (IBS).
Among other things, Crohn disease is since the barrier function of enteric epithelium is interfered.Mucus on intestinal mucosa, which is shown, to be lacked Weary anti-infection property alexin.Due to the disorder of barrier function, enteric bacteria penetrates into intestinal wall and causes inflammation, and then causes to barrier Further damage.Therefore, previously described to help to prevent Crow grace by N- acetyl diaminobutyric acid reinforcing barrier function Disease treats the disease.Similarly, the enhancing of barrier function is also on a kind of ulcerative colitis (chronic inflammatory intestines for influencing large intestine Disease) it brings and is obviously improved.
The treatment of gastroesophageal reflux disease
Containing N- acetyl diaminobutyric acid, the salt of N- acetyl diaminobutyric acid or the composition of ester can also be used for treating And/or prevent the method for gastroesophageal reflux disease, stomach or duodenal mucosa inflammation and damage and/or stomach or duodenal ulcer In.Gastroesophageal reflux disease can be reflux esophagitis, Non-erosive reflux diseases or Barrett oesophagus.
Gastroesophageal reflux disease (GERD), it is also referred to as heartburn (heartburn), be it is a kind of frequent occurrence the phenomenon that.In western industrial Change country, which at least occurs weekly primary in the adult for accounting for about adult population 10% to 20%.In East Asia, illness Rate has 20% to be affected weekly, even has 7% daily by shadow between 2.5% to 7.8% in the U.S., adult population It rings.The fact that the disease mainly enters esophagus due to the gastric acid from stomach.In addition to gastric acid, other gastric contents enter esophagus It works, such as digestive ferment pepsin, is a kind of for digesting the peptase of protein in food.Pepsin strengthens stomach The destruction of acid.
For those impacted people, this disease is a very big burden, is on the one hand because it can cause The sharply burning sensation of esophagus, be on the other hand because it be beastly in people's everyday exposure, because of acid belch It is difficult to control.Under normal conditions, patient can feel burning heat sensation or even reachable throat.The most common treatment choosing generallyd use Select is using proton pump inhibitor (PPI), such as Omeprazole and its amine salt bisfentidine (H2Ra).Two kinds of substances all purports In the generation of gastric acid inhibitory.Another therapeutic choice is administration antiacid, i.e. gastric acid neutralize material.Alginates can be formed under one's belt Viscous foam prevents gastric acid reflux into esophagus.
Gastroesophageal reflux disease is usually related with cardia insufficiency.This is the dysfunction of sphincter (sphincter of gullet), It separates esophagus and stomach, and gastric content is caused to flow back to esophagus.Other reasons may include excessive gastric acid generation or esophagus is compacted Dynamic defect.The problem especially frequently occurs at night, i.e., when patient is in clinostatism.In addition, dessert or smoking and drink can Promote the appearance of reflux symptom.
Gastroesophageal reflux disease can behave as Non-erosive reflux diseases (NERD), wherein Esophageal mucosa injury is not found, Also it can be used as erosive reflux diseases (reflux esophagitis；Erosive esophagitis (EE)；Erosive reflux disease (ERD)). In the latter, the mucous membrane in esophagus changes and can detecte mucosa injury.Transitional region between stomach and esophagus Bleeding and ulcer may occur.Another complication of gastroesophageal reflux disease may be esophageal stricture, this causes again in turn Dysphagia.
The further stage may be Barrett oesophagus (interior short esophagus), wherein it can be observed that the metaplasia of epithelium of esophagus Conversion, the multilayer scaly epithelium of oesophagus are converted into the prismatic cylindrical epithelium of single layer of remote area.This transformation can be in Whole annular, especially in stomach oesophagus transitional region, i.e., from stomach to esophagus tube transitions.Although cylindrical epithelium is to gastric acid stomach function regulating Enzyme-pepsin has stronger resistance, but there are still hypogenetic risks.Therefore, Barrett oesophagus may be oesophagus The primary stage of cancer (Barrett cancer) development, it is therefore necessary to go through and monitor.In addition, Barrett oesophagus may cause it is routed Ulcer is formed.
It has been found that N- acetyl diaminobutyric acid and its respective salt and ester can be obviously improved gastroesophageal reflux disease And pyemia.It can prove that N- acetyl diaminobutyric acid can reduce acid and pepsin to the negative shadow of squamous cell It rings.
It has also been found that the damage to stomach or enteric epithelium can be prevented and treated with N- acetyl diaminobutyric acid.This is especially suitable For treating and preventing gastritis.Aggressivity gastric acid can attack gastric mucosa, for example, protectiveness rete malpighii generation by outside In the case where the interference of factor.Therefore, also due to the improvement of the barrier function of epithelium, In the effect of N- acetyl diaminobutyric acid It in this case is the epithelium in stomach, esophagus and intestines.It has been found that N- acetyl diaminobutyric acid and its derivative can prevent With treatment gastritis.Reflux esophagitis can lead to gastritis.
Gastritis can lead to the formation of gastric ulcer (ulcus ventriculi), and gastric ulcer is finally also viscous in stomach wall stomach function regulating Film fails for gastric acid and since aggressivity gastric acid causes in the case where being still adequately protected.For example, one of damage factor is Gastric acid excess generation.In general, the formation of gastric ulcer is especially attributable to the damage etc. of gastric mucosa；In this respect, gastric mucosa is protected Additionally provide anti-gastric-ulcer protection.
N- acetyl diaminobutyric acid is also possible to prevent the damage to duodenal epithelium, this is why these substances It is very suitable to the reason of preventing and treating the inflammation of duodenal mucosa.Similar with gastric mucosa, duodenal epithelium is single layer circle Columnar epithelium.Duodenum is the first part of the small intestine of neighbouring stomach.Since it is exposed to the gastric content of high corrosiveness, institute It states gastric content to mix with digestive ferment such as pepsin, it may occur however that the inflammation and damage of duodenal mucosa.In addition, coming from liver Dirty and gall-bladder bile and pancreatin are supplied to the food in duodenum.Duodenal mucosa damage can lead to duodenum and burst Ulcer (ulcus duodeni) influences the life of about 2 to 10% people.The development of duodenal ulcer is also based on attack mucous membrane Substance (such as gastric acid and certain protease) and protect the factor such as enough mucus of mucous membrane formed between imbalance.Cause This, protection duodenal mucosa is of great significance for preventing and treating duodenal ulcer.It has been found that mentioned above N- acetyl diaminobutyric acid and its derivative are effectively used for prevention purpose, to prevent the hair of gastric duodenal ulcer Exhibition, and it is further used effectively for treatment stomach/duodenal ulcer.Even if it is smaller to the damage of stomach/duodenal mucous membrane and Not yet lead to the development of ulcer, also can treat and prevent any damage (erosion) occurred in this region.
Composition of the invention can be used for treating and/or preventing the septicopyemia of gastroesophageal reflux disease or different severity Disease Non-erosive reflux disease and wherein has been detected by the reflux esophagitis of Esophageal mucosa injury.Therapeutic choice packet Barrett oesophagus is included, this is a kind of serious disease relevant to risk of cancer increase.
In general, composition is aqueous solution, in most cases for being administered orally.
It is damaged the recovery of bodily tissue
Another aspect of the present invention relates to salt or ester containing N- acetyl diaminobutyric acid, N- acetyl diaminobutyric acid Composition, be used to treat and/or restore to be damaged in the method for bodily tissue.This specifically can be wound or ulcer.
Bodily tissue may be damaged in various ways.Tissue damage is particularly likely to occur by external action, i.e., due to Traumatic event causes.In general, this tissue damage, especially in skin or mucosal areas, also referred to as wound.In addition to it is external because Outside tissue damage caused by element, atraumatic damage is also referred to as ulcer.
It can also happen that injury to bodily tissue during ophthalmic surgical and endoscopic surgery and interventional therapy.With it is outer Section interventional therapy is related, often will appear so-called post-operation inflammatory stress and pain, this may cause the master that patient must cope with Want problem.This inflammatory stress be usually the mechanical stress as caused by interventional therapy as a result, and not necessarily must be with intervention Target itself is related.Post-operation inflammatory stress usually occur during abdominal operation, especially in the gastrointestinal tract, but also see liver With during the interventional therapy and endoscopy of kidney.For example, mechanical stress is due to needing during operation in abdominal cavity Mobile intestinal loop expands abdominal cavity, or especially when being checked, applies due to pressure to intestines itself or abdominal cavity.By these work Inflammatory phenomena caused by dynamic and stress may last very long after surgery once in a while with pain with their inflammation.It is this Situation correspondingly applies to the operation executed in other regions of body, such as has tooth pulled out in dentistry, Jaw Bone Operation or treatment bone During interventional therapy needed for folding.Among other things, such case is also applied for having tooth pulled out, Jaw Bone Operation and tooth and joint prosthesis Implant surgery and operated eye.
In general, after injury occurs soon, the Natural re generation of impaired bodily tissue has begun.Having resulted in wound In the case of, blood clotting very rapidly starts, and causes impaired blood vessel by clottage.In the subsequent exudation stage, seep Liquid exudation out causes foreign matter and bacterium to be discharged from wound.Immune system attack simultaneously kills bacterium.
In the subsequent multiplicative stage, new connective tissue is generated, thus filling defect as caused by wound.Finally, again In the raw stage, the epithelial cell undue growth grown from the intact epithelial tissue in edge of wound region is to be closed the wound.
Although smoothly natural wound healing relatively usually occurs in the case where wound is less big, serious and big Complication is likely encountered in the case where wound, especially as excessively forming complication caused by exudate.This is equally applicable to respectively The ulcer of seed type.In addition, the chronic wounds as caused by permanent pressure (bedsore) or the wound healing as caused by diabetes Delay is considered particularly troublesome.It is comprehensive that patient with latter disease possibly even develops so-called diabetes Sign, have three in all amputation cases of Germany/second is that as caused by diabetic foot syndrome.
Within the scope of the invention, the body that it can be promoted to restore by the composition containing N- acetyl diaminobutyric acid Body tissue specifically can be skin or mucous membrane.Injury substantially can be traumatic.This be understood to mean that damage be by It caused by external action, such as hits, hurts, shouting pain is bitten.Such mechanicalness wound may be by for example due to accident Caused by or surgical operation result.
The impaired situation of mucous membrane can also refer to catarrh, and treatment also belongs to the scope of the present invention, be related to promoting impaired body The recovery of body tissue.Catarrh may have the different causes of disease.Since the regeneration rate of mucomembranous cell is high, catarrh is often sent out It is raw, for example, the side effect as the treatment of cancer during chemotherapy or radiotherapy.In addition, the immune system of reduction, such as The patient of immunologic hypofunction will lead to infection and increase, and then may cause mucosa irritation.Especially oral mucosa and gastrointestinal tract Mucous membrane may be affected.
Other than mechanicalness wound, there is also the tissue damages of other properties, can also use combination proposed by the present invention Object treatment.These include for example the fire due to heat, and temperature (thermal) caused by scald or pernio is hurt, burn, chemical burn or The wound as caused by ionising radiation.
Other than wound, contusion/bruise can also be treated by means of composition of the invention.In the case where bruise, Organ or physical feeling are damaged by mechanical force and skin itself preserves from.From the capillary of damage to the blood of surrounding tissue It leaks particularly evident in the form of hemotoncus.
Other than promoting the recovery of impaired bodily tissue in the case where causing the damage by external action, the present invention The composition of proposition is also applied for treatment ulcer.Ulcer may have different reasons, such as circulation system disease, tumour or sense Dye.The example for the ulcer that can be treated with the help of composition proposed by the present invention is leg ulcer (" ulcer leg "), bedsore (pressure sore), malum perforans pedis (foot pressure ulcer), chancre (ulcus durum), chancroid (ulcus molle) are invaded Corrosion ulcer (ulcus rodens), ulcer of the cornea (ulcus corneae) etc..
The composition acquires a special sense for treatment chronic injury, especially chronic wounds or chronic ulcer.Herein An example be diabetic foot syndrome (DFS), be colloquially called diabetes.In this respect, slight injury, especially Foot or shank, it will usually which healing is healed without complication, but since diabetic is easy to happen poor wound healing Time is usually longer.Poor wound healing is especially because the dyshaemia that diabetic occurs.Diabetic foot syndrome It is characterized in ulcer, may spreads and be deep into corresponding body region, and has the additional wind for the infection that bacteria-induction occurs Danger.Due to annual because diabetic foot syndrome needs the number of amputation larger, this, which to provide effective therapeutic choice, becomes It is necessary and desirable.
The known recurrent tissue damage of another kind is bedsore (decubital ulcer, pressure sore).Simultaneously in particular for nursing And the people of limited bed suffers from bedsore since pressure is applied to for a long time on certain positions of body.If acted on blood vessel Pressure is more than the capillary pressure of blood vessel, then insufficient amount of oxygen and nutriment are transported to cell, eventually leads to tissue damage Wound.Pressure ulcer does not occur in Healthy People usually, because they often change position, to alleviate skin region in imminent danger Domain, but the necessary reflection of caregiver is needed to be restricted or only exist on limited extent.Especially bone particularly near Bedsore may occur for the skin area of skin surface.Open decubitus ulcer is also possible to allow microbe infiltration.In view of needs The number of nursing is numerous and serious consequence caused by bedsore, the especially needed beneficial therapeutic scheme of such case occurs.
Another example of medicable ulcer is aphtha.Aphtha is with the painful damage to the mucous membrane in oral cavity and larynx Form occurs.The reason of leading to aphtha, is still largely without method interpretation.Particularly, if for example they occur in high stress Region, then recurrent aphthous ulcer may be very painful for patient.
Other damages that the bodily tissue of composition proposed by the present invention can be used are hemorrhoid damage or anal fissure, big Caused in most cases by mechanical stress.In general, can be by mitigating itch, inflammation and pain come the side in the present composition Help lower treatment hemorrhoid.
Promote impaired bodily tissue recovery be also it is beneficial because the formation of scar can be prevented in this way. It has been observed that the healing of wound, especially skin wound is improved, so as to avoid because of light by applying composition of the invention It learns reason and forms undesirable scar.
Component as organ preservation solutions
According to another variant, the present invention relates to containing N- acetyl diaminobutyric acid, N- acetyl diaminobutyric acid The composition of salt or ester is used as saving transplant organ, the use of the component of the preservation solution of transplant organ system or transplanting tissue On the way.
Being implanted in modern medicine for organ, especially kidney, heart, liver, pancreas and lung plays an important role.Organ Transplanting may be necessary, for example, in the case where the certain coronary heart disease of chronic renal failure or cirrhosis.Most of transplanting are It is carried out using the organ of brain death donor, it is suitable, by certain time, to need to find during this period after organ removes Recipient and be prepared, this to need to save corresponding organ.Therefore, corresponding organ keep within a certain period of time with The cutting of oxygen supply, i.e., it pass through ischemic stage relevant to related reversible lesion.In general, organ is in the temperature down to about 4 DEG C Degree is lower to be saved or transports.Other than the damage caused by ischemic itself, when low temperature organ is heated and uses blood reperfusion, It can also happen that so-called reperfusion injury.
When removing organ, it will usually be rinsed and be stored in primer solution with primer solution.Commonly solution is So-called UW solution (University of Wisconsin), the ion concentration provided correspond to the concentration in cell.What is be commonly used is another Kind organ preservation solutions are HTK solution, by the Franz of German ChemieGmbH BensheimDoctor is with trade name Custodiol is sold on the market.Abbreviation HTK represents solution composition histidine, tryptophan and α-ketoglutaric acid.In addition, another The well-known organ preservation solutions of kind are distributed with trade name Celsior by Genzyme, Cambridge USA.
It has been found that by the way that N- acetyl diaminobutyric acid is added into preservation solution, it is possible to reduce saved to being stored in The damage of organ, tissue and tract in solution and with preservation infusion.It is preferable to use HTK solution conducts herein Base fluid contains the preservation solution of histidine, tryptophan and α-ketoglutaric acid or respective salt.
The concentration of N- acetyl diaminobutyric acid should be 0.1 between 100mM.Preferred concentration range is 1 to 10mM, special Not You Xuanwei 4 to 7mM, most preferred concentration is about 5mM.At various concentrations, it is noted that organ damage/impaired has significantly reduced.
Common HTK aqueous solution contains:
HTK solution Principle is based on the discharge by extracellular sodium and calcium and passes through histidine/histidine hydrochloride buffering Extracellular environment inactivates organ dysfunction.In this way, extend what the organ when supplying oxygen blood supply and interrupting was resistant to Period.The electrolyte composition of HTK solution inhibits the triggering of energy consumption activation, so that reducing the energy of organ needs It asks.Histidine/histidine hydrochloride buffer slows down the decline of pH during ischemic, this efficiency for causing anaerobic energy to recycle obtains Improve.Bottom of the α-ketoglutaric acid monopotassium salt (potassium hydrogen2-ketoglutarate) as aerobic energy regenerating Object, tryptophan have film protective effect, and mannitol is used to prevent the development of edema.Pass through N- acetyl group two shown in addition The amount of aminobutyric acid can optimize the property of this solution.
Also there is similar effect when being added to UW solution, the trade name of the UW solution is also referred to as Viaspan.The group It closes species and is similar to intracellular cytosol.Among other things, the solution be based on metabolisable inert matter such as lactobionic acid or associated salts or The principle of gossypose maintenance osmotic concentration.Hydroxyethyl starch is for preventing oedema.Furthermore, it is possible to which free radical can be removed by adding Substance.
Common UW aqueous solution includes:
Finally, the property of Celsior solution can also be improved by adding N- acetyl diaminobutyric acid.The solution contains Mannitol, newborn diacid, glutamic acid, histidine, calcium chloride, potassium chloride, magnesium chloride, sodium hydroxide and glutathione etc..
Common Aquo-composition contains:
The present invention is especially suitable for kidney, heart, lung, the transplanting of liver or pancreas.However, it is also possible to save group to be transferred It knits, such as cornea or tract, such as finger or hand.
Solution is saved, especially when it is based on HTK solution, may include other groups well known by persons skilled in the art Point.In this respect, with reference to European patent EP 1 362 511 B1 and 1 859 679 B1.Specifically, preservation solution can contain different Hydroximic acid or hydroxamic acid derivs, the derivative depend on the circumstances as the substitution of alkyl-substituted or aryl.It is particularly suitable for Be Deferoxamine, it is a kind of strong iron chelating agent, has the function of up to three hydroxamic acid.In this way, it is therefore prevented that with iron Relevant cold-induction damage.Substantially, other iron chelating agents also can be used.It can be based on N- acyl group histidine, specifically N- Acetyl-histidine and related base use buffer.
Lysine, arginine or glycine or related derivatives can be contained, such as containing lysine, arginine or glycine Dipeptides.This is equally applicable to other natural amino acid alanine, valine, leucine, isoleucine, methionine, proline, Phenylalanine, tryptophan, serine, threonine, asparagine, aspartic acid, glutamine, glutamic acid, tyrosine, half Guang ammonia Acid and histidine.Basic amino acids lysine and arginine or derivative can be used as alkaline equivalent.
Equally it is beneficial that the addition of aspartic acid, supports the mass exchange on film and accelerate the recovery of homeostasis, And it is combined with α-ketoglutaric acid, advantageously the aerobic energetic supersession during influence Reperfu- sion phase.
For the energy requirement of organ during meeting ischemic, glucose can be added in storage solutions.In this feelings Concentration of glucose must be properly selected under condition, to avoid other cell excess ingestion glucose.Also other sugar, sugar can be used Alcohol or other polyalcohols (such as mannitol, gossypose, sucrose, xylitol, D-sorbite) or polymer substance such as HES or Portugal Glycan, to reach the required reason osmotic pressure of about 300mosm/l.
Dimethyl sulfoxide (DMSO) can be used as cryoprotector.Such as Trolox (6- hydroxyl -2,5,7,8- four can be used Methyl chroman -2- carboxylic acid) free radical scavenger intercept intracellular free radicals.
Preservation solution proposed by the present invention can be not only used for organ, the storage of tissue or tract, Er Qieke certainly For from the perfusion purpose during donor harvesting organ.In general, organ with infusion is saved, is then saving solution Middle storage and transport, until it is implanted into receptor body.
Treat cellular senescence process
In general, containing N- acetyl diaminobutyric acid, the salt of N- acetyl diaminobutyric acid or the composition of ester also be can be used In treatment and/or prevention cell senescence symptom.In this respect, NADA can become the useful component part of anti-aging product.
The treatment of ear disease
Ear disease, the i.e. damage of ear field can also be used and contain N- acetyl diaminobutyric acid, N- acetyl group diamino fourth The salt of acid or the composition of ester are treated.This includes in particular otitis externas, the i.e. inflammation of external ear.It is characterized in that pain, itch, It is rubescent, it the scales of skin that peel off and crusts to be formed and be secreted.These reasons usually initially have engineering properties, therefore slight damage may with Bacterium infection afterwards is related.It can also happen that bacterium infection, the bacterium such as pseudomonad after swimming or diving.Other bacteriums Pathogen is staphylococcus.Otitis externa it is viral, anaphylaxis or immune background context are also possible.
Ear field may undergo another kind it is offending feel it is itch, that is, itch.This is usually by histamine or other letters Cause the release of substance, especially mast cell.The itch of other forms outside ear can also be controlled according to the present invention It treats.
General remark
No matter its application, the composition can be for example with solution, flushing liquor, suspension, ointment, emulsifiable paste, lotion, paste The form of agent, lotion, microemulsion, spray, jelly or aerosol uses.In the case where lotion and microemulsion, these can To be oil-in-water (O/W) or Water-In-Oil (W/O) emulsion/microemulsion.
With or without carrier of the Aquo System particularly suitable as liquid dosage form of buffer.For viscosity or semisolid The suitable carrier substance of preparation, such as ointment, emulsifiable paste or gel, are paraffin hydrocarbons, vaseline, wool wax product and other pharmaceutically acceptable Thickening basic material, and be used for hydrophilic gel, such as water, glycerol.Or D-sorbite, suitable sweller example can be used As polyacrylic acid, cellulose derivative, starch or bassora gum are gelled.
Ointment, paste, emulsifiable paste and gel are fatty containing conventional carrier mass, such as animal and plant, wax, paraffin, Starch, bassora gum, cellulose derivative, polyethylene glycol, siloxanes, bentonite, silicic acid, talcum and zinc oxide or these substances Mixtures/blends.
In order to improve application and the shelf-life of composition according to the present invention, the composition containing active constituent also be can wrap It is enclosed in nanostructure or is administered in the form of liposome.If composition is free of any preservative, this is particularly advantageous.With It is usually well known in the prior art in the appropriate method of encapsulating.
Other than active constituent that may be present and carrier mass and any emulsifier, preparation of the invention can be with Containing other harmless drug excipients and/or additive compatible with active material, for example, filler, diluent, bonding Agent, wetting agent, stabilizer, coloring agent, buffer, odoring substance and/or preservation substance, fungicide, solubilizer, vitamin, surely Determine agent, prevents the substance of foaming, thickener, colorant, surfactant, moisturizing materials, emulsifier, tackifier etc..
For example, preservative agent includes thimerosal, organomercurial compound, such as phenyl mercury, and benzalkonium chloride, Chlorhexidine, benzyl alcohol, Glucose, ethyl alcohol and quaternary ammonium salt.
The example of tackifier is cellulose ether, such as hydroxyethyl cellulose, carboxymethyl cellulose, hydroxypropyl methyl fiber Element, methylpropylcelluloses, methylcellulose, methylethylcellulose, ethyl cellulose, hydroxyethylmethylcellulose, hydroxypropyl Base cellulose, ethylhydroxyethylcellulose.Other examples include polyethylene glycol, polyvinyl alcohol, polyvinylpyrrolidone, and osamine is poly- Sugar, proteoglycan, hexadecanol and stearyl alcohol, or combinations thereof (cetyl stearyl alcohol), polyacrylic acid, polymethylacrylic acid, Polyacrylamide, polyethers, polyimides, polyamide, alginates, xanthan gum, polyuronide glycosides, alginic acid, carragheen, chondroitin sulfate Element, guar gum, hydroxypropyl guar gum and starch acetate.
The concentration range of tackifier is preferably 0.05-10wt% in composition, preferably 0.1-3wt%.For example, it was discovered that following Concentration range is suitable: the concentration range of cellulose ether is 0.2 to 2.5wt%, the concentration range of polyethylene glycol be 0.2 to 1wt%, the concentration range of polyvinyl alcohol are 0.1 to 4wt%, and the concentration range of polyacrylic acid is 0.1 to 4wt%, polyacrylic acid Concentration range be 0.1 to 0.3wt%.
Moisturizer or moisturizing materials are such as glycerol, D-sorbite, trehalose, glycine betaine, Dexpanthenol, 1,2-PD, Xylitol or other polyalcohols.
The composition can contain other active components.For example, N- acetyl diaminobutyric acid above-mentioned or related derivatives It can be combined with one or more substances selected from the following: Dexpanthenol or derivative, Arnica extract (Arnica (arnica)), capsaicine, pepper extract, Hypericum Perforatum P.E (St John's wort), cardiospermum halicacabum (cardiospermum halicacabum) (balloon strain), hamamelis extract (witch hazel), tocopherol, allantoin, opopanax Alcohol, cocoa extract, silver, nano silver, micron silver, amorphous silver, silver salt, zinc, zinc oxide, calendula extract (pot marigold), Honey and Mel extract, propolis, daghestan sweet clover (melilotus officinalis) extract, Radix Arnebiae extract (Sambucus thunbergiana (symphytum)), blueweed (echium vulgare) extract, dill seed, Radix Angelicae Sinensis (angelica sinensis) extract, Ferulic acid (ferulic acid), hyaluronic acid, aloe extract, german chamomile (matricaria recutita) (chamomile) mention Object is taken, onion (onion) extractive form corm, alpine yarrow (achillea millefolium) extract (milfoil (yarrow)), swollen fruit is sweet Careless extract (licorice (licorice)), licochalcon A, organosilicon, urea, Echinacea (purple coneflower) extract, Cichoric acid (chicoric acid).
For example, other active components can be other compatible solutes.Specifically two Myo-Inositol phosphate (di-myo- Inositol phosphate, DIP), ring 2,3- ester diphosphoglycerate (cDPG), 1,1- bis- glycerophosphate (DGP), β-is sweet Reveal glycoglyceride (Firoin), β-mannose group glyceramine (Firoin) A), two mannose groups, two myo-inositol phosphates (DMIP), Glucose glycerol, taurine, glycine betaine, citrulling, 4,5- dihydro -2- methyl-imidazoles -4- carboxylic acids (DHMICA) and 4,5,6,7- Tetrahydro -2- methyl-1 H- [1,3]-diaza -4-S- carboxylic acid (high oleic acid) and relevant derivative, specifically salt, ester or amide. Other suitable active constituents are local anti-inflammatory medicine, such as steroids, cyclosporin A, beta-blocker.It is suitable for use of It is and antipruritic substance, antifungal agent, inhibitor, fungicide, the combination of antivirotic and therapeutic peptide.
The composition can also contain antibiotic.This includes gentamicin, kanamycins, neomycin, tobramycin, cyclopropyl sand Star, Ofloxacin, duomycin, Ciprofloxacin, erythromycin, Fusidic Acid, Lomefloxacin, lavo-ofloxacin and terramycin.
It enables to adjust to specific pH value furthermore it is possible to provide pH buffer system to composition.Suitable buffering System is citrate, phosphate, TRIS, glycine, borate, acetate.These buffer systems can by such as citric acid, The substance of sodium dihydrogen phosphate, disodium hydrogen phosphate, glycine, boric acid, sodium tetraborate, acetic acid or sodium acetate generates.
Generally, based on the total weight of composition, the concentration range of N- acetyl diaminobutyric acid is 0.001 to 50wt%, It is preferred that 0.05 to 20wt%, specifically 0.1 to 10wt%.
Embodiment 1: humidifying effect
N- acetyl group diamino is studied using Matsuo moisturizing test (Matsuo, Br J.Opthalmol.85:610-612) The skin of base butyric acid/mucous membrane moistening effect.The SIRC cell line separated from lagophthalmos is for this purpose.For experiment, by 30,000 A cell is placed in each hole of 96 hole microtiter plates.After about 24 hours, complete single layer is formed in each case.So After remove supernatant, 100 μ l are applied on cell 15 minutes with PBS (phosphate buffered saline) diluted test substances. Then, supernatant is removed again.In this stage, cell is washed without PBS.Aseptically, by cell in 45 minutes wind It is dry.Hereafter, cell is washed three times with PBS.In order to determine cell viability, (calcein-acetyl oxygen is dyed using Calcein-Safranine T Ylmethyl ester).Calcein is a kind of fluorescent dye.After Calcein-Safranine T is transported in living cells, ester group is by cell Esterase cracking, leads to the formation of calcein, to generate the strong green fluorescence compound formed with calcium ion present in cell. Therefore, high fluorescence represents the high vigor of cell, because dead cell does not have the activity that can discharge compound required calcein Esterase.In turn, high cell viability demonstrates the good wettability of test substances.
As a result as shown in Figure 1 compared with the effect of Ectoin and hyaluronic acid.It is shown using the test of 25mM NADA With the comparable result of Ectoin as reference substance.In the figure, with the control group of undried processing (IF=100%) It compares, it can be seen that the wetting after the vigor of cell and therefore dry cell.In addition, being compared for hyaluronic acid (HA) Compared with.Optimal wetting effect is realized using 10 to 50mM NADA.
Embodiment 2:UV and IR protection
A: it is measured by TEER and carries out ultraviolet protection test
Epithelium layer and endothelial layer are characterized in that the formation of Cell tracking, cause intensive barrier cell will Substrate side (nearly chamber) side is separated with top (chamber) side.Cellular layer forms the permeable interface of selectivity between different compartments, with This mode controls diffusion and intracellular transport process in space between cells.This is by closely connection (in intercellular space Barrier by cell) ensure.The integrality of these barriers is determined by so-called TEER method (transepithelial/across transendothelial electrical resistance).It will The D/C voltage of restriction is applied to two electrodes of battery layers two sides.The electric current for measuring flowing, obtains accordingly according to Ohm's law Resistance result.
User's keratinocyte cell line HaCaT cell.They are applied to PET filmIt waits Cell forms complete and complete single layer.The integrality to confirm single layer can be measured by TEER value.If the value is in 2 days Do not increase, then assume that cell has formed stable single layer and has been ready for testing.
In order to study the protective effect radiated by the stable film of N- acetyl diaminobutyric acid to UV deeper into ground, by angle egg Leucocyte overnight incubation in containing PBS, NADA (50mM and 100mM) and the cell culture medium of other compounds.Hereafter, will Cell is exposed to uv b radiation 45 minutes.Cell is further cultured for 24 hours, TEER value is measured.As the result is shown in Fig. 2.It is sat vertical On parameter, the variation of TEER value is indicated after uv b radiation with %.
The sharply decline of TEER value shows that film is interfered.As can be seen that untreated cell after uv b radiation exposure There is being substantially reduced for about 15% TEER value in (" untreated control ").It, can be with however, in the presence of 100mM NADA Observe the obvious protection to cell membrane.
B: test is protected using the UV of LDH measurement
The ultraviolet radiation protective effect of NADA for further evaluation has used the full thickness of Henkel (Phenion skin model) Spend skin model.This is to be based on bovine collagen protein structure, suitable with human skin in form, therefore can be easy to carry out inspection It looks into.Phenion skin model is incubated 4 hours together with test substances.These directly apply to top surface.Then, will Phenion skin model is exposed to uv b radiation 2 hours.The time span of selection is longer than individual cells layer, because of Phenion skin The resistance of skin model is considerably higher.Then skin model is incubated to 24 hours again and measured LDH (lactic dehydrogenase) value, be pair The measurement of degree of injury caused by cell.From figure 3, it can be seen that the LDH value before UV exposure is for PBS and NADA substantially phase Together, the PBS control after finding UV exposure is apparently higher than LDH value.Generally speaking, NADA is based on TEER thus it is shown that being similar to UV protection feature determined by the cellular layer model of measurement.
C: test is protected using the IR of LDH measurement
Infrared (IR) radiation causes skin temperature to increase, the increase and heat shock induction metalloprotein of this and free radical quantity The expression of enzyme (MMP) increases related.Being exposed permanently to IR radiation may cause cell mortality to increase by Apoptosis.In order to Determine the ability of NADA and Ectoin for comparative purposes to eukaryocyte from heat and the protective effect of IR radiation, it will HaCaT cell (Human keratinocytes system) is applied to 96 holes of microtiter plate.After forming uniform cellular layer, it will survey Examination substance is applied on culture medium, and by cell incubation at temperature 5 hours of 37 DEG C.After precincubation, 44 DEG C are exposed cells to Temperature 30 minutes.Then cell is incubated 60 hours again at 37 DEG C.It is then based on the release of supernatant fluid inspection LDH；As a result it shows Show in Fig. 4.As can be seen that NADA and Ectoin both provide the guarantor for fighting strong IR radiation compared with untreated cell Shield, and verified NADA is more more effective than Ectoin.
Embodiment 3: film stabilizes
Membrane stabilizing action is checked using TR146 cell line and therefore reinforces the barrier function of epithelial cell by NADA. TR146 cell line is people's cheek cell line of oral mucosa cell.Cell is placed in the microtiter plate with 96 holes.Once reaching To converging, wash cell with PBS and provide the N- acetyl diaminobutyric acid of various concentration.Negative control only contains PBS, positive It compares cDPG (cyclic annular 2,3- ester diphosphoglycerate).After incubation, wash cell with PBS again, and with 5 μM of Calcein-Safranine Ts one It rises and incubates 45 minutes.Calcein-Safranine T (being non-fluorescence) generation calcein in itself, Yi Zhongqin are hydrolyzed by intracellular esterase Water, high fluorescent chemicals, are retained in the cytoplasm of cell.Therefore, high fluorescence indicates high cell viability.With only use PBS The cell of processing is compared, and causes the apparent concentration dependent of epithelial cell to stabilize with NADA pretreatment.As a result as shown in Figure 5.
Fig. 6 shows the corresponding experiment using LLC-PK1 cell line, and the experiment, which accidentally corresponds to, has above-mentioned TR146 The experiment of cell line, in this case, Ectoin additionally may act as reference material.Herein, the membrane stabilizing action of NADA can To be proved well.
Influence of the embodiment 4:NADA to cell metabolism
ATP measurement is for proving influence of the N- acetyl diaminobutyric acid to cell metabolism and therefore it is old to anti-cell Change the serviceability of phenomenon.HaCaT cell (keratinocyte cell line) is placed on 96 hole microtiter plates, cell culture shape is made At at least one week time, until terminating cell growth by contact inhibition.Then, then by cell culture one week to simulate aging Process.Cell culture medium is changed to PBS, NADA and reference material such as glucose base glycerol, Ectoin is added (28Extremoin) andA kind of commercially available anti-aging product.By cell culture 5 hours.Finally, preparation ATP Measuring method, wherein high ATP synthesis shows hypermetabolism degree and hence it is demonstrated that cell viability.It as a result can be as seen from Figure 7.With NADA processing causes aging cutin to form the reactivation of cell, and can be reflected in compared with the cell only handled with PBS (0%) can In the ATP activity of measurement.
Embodiment 5:NADA is on close-connected influence
Check the up-regulation for concentrating on tight junction protein, the tight junction protein is the component part as close-fitting vest connection Memebrane protein closing epithelial cell between gap to forming barrier.The barrier controls infiltration of the molecule by epithelial cell. Specifically, detection hole enclosed type tight junction protein -1.The expression increase of tight junction protein -1 leads to the impermeable of epithelial membrane Property increase and transepithelial electrical resistance (TEER) increase.Therefore permeability is reduced.
The epithelial cell line (HaCaT) for being used to test is cultivated in the hole on microtiter plate, until forming closed pore list Layer.Then, it is used NADA pretreatment cell 6 hours in cell culture medium (10,25,50,75,100 and 175mM).It then will be thin Cytoplasmic process is so exposed to temperature 30 minutes of 44 DEG C, then keeps 24 hours and 48 hours again at 37 DEG C respectively.Harvest cell simultaneously makes With -1 specific ELISA of tight junction protein (enzyme linked immunosorbent assay (ELISA)) analytical pyrolysis object.It as a result can be as seen from Figure 8. Behind 24 hours and 48 hours, it can be observed that the expression of tight junction protein -1 obviously increases, this leads to more dense epithelium And thus increased barrier effect.
The preparation of embodiment 6:N- acetyl diaminobutyric acid (NADA)
The Ectoin of 207g is dissolved in the KOH solution (2M) of 2L and is stirred at room temperature 19 hours.It is thus obtained Solution is neutralized with 25%HCl；KCl is removed by electrodialysis.It is concentrated and is dried to obtain below the product of colourless powder form.Reaction Product contains the Ectoin less than 1wt%, and by (2S) -4- acetylaminohydroxyphenylarsonic acid 2-amino-butyric acid and 20wt% of 80wt% (2S) -2- acetylaminohydroxyphenylarsonic acid 4-Aminobutanoicacid composition.

Claims (26)

  1. The ester of 1.N- acetyl diaminobutyric acid, the salt of N- acetyl diaminobutyric acid or N- acetyl diaminobutyric acid, is answered For in the method for treating human body or animal body.
  2. 2. the composition containing N- acetyl diaminobutyric acid, the salt of N- acetyl diaminobutyric acid or ester is used for In the method for treating human body or animal body.
  3. 3. the composition containing N- acetyl diaminobutyric acid, the salt of N- acetyl diaminobutyric acid or ester is used for In treatment and/or prevention dry skin or the method for mucous membrane drying.
  4. 4. the composition of purposes according to claim 3, it is characterised in that the mucous membrane is schneiderian membrane, oral mucous membrane, eye mucosa or Vagina mucosa.
  5. 5. the composition of purposes according to claim 3 is applied in the method for treating atopic eczema.
  6. 6. the composition containing N- acetyl diaminobutyric acid, the salt of N- acetyl diaminobutyric acid or ester is used for Protect application on human skin or mucous membrane from the method in physics, chemistry and/or the method for biotic influence or for treating catarrh.
  7. 7. the composition of purposes according to claim 6, for protecting application on human skin or mucous membrane to anti-visible-light, UV and/or IR spoke It penetrates.
  8. 8. the composition of purposes according to claim 6, for protect application on human skin or mucous membrane to anti-allergen, heat, irritation or Oxidizing substance promotees denaturation substance, particulate matter and/or free radical.
  9. 9. the composition containing N- acetyl diaminobutyric acid, the salt of N- acetyl diaminobutyric acid or ester is used for Treatment and/or prevention psoriasis, seborrheic eczema, rosacea, nettle rash, actinic keratoma, skin disease, contact are wet Rash, moss, ichthyosis, diaper dermatitis, diaper rash, rubefaction, swelling, blistering, rubeola, exfoliating skin, patch, alopecia or head In the method for burnt hair.
  10. 10. the composition containing N- acetyl diaminobutyric acid, the salt of N- acetyl diaminobutyric acid or ester is used for Enhance tissue assembling in cell power of regeneration and/or reduce cellular aging process method in.
  11. 11. the composition containing N- acetyl diaminobutyric acid, the salt of N- acetyl diaminobutyric acid or ester is used for In the method for the treatment of and/or prevention respiratory disease.
  12. 12. the composition of purposes according to claim 11, it is characterised in that the respiratory disease is the particulate matter by suspending Caused by the effect of matter, specifically pulmonary disease.
  13. 13. the composition of purposes according to claim 11, it is characterised in that the respiratory disease is the breathing of allergy induction The respiratory disease of tract disease or virus induction.
  14. 14. the composition of the purposes of any one of 1-13 according to claim 1, it is characterised in that the respiratory disease is allergy Property rhinitis, anaphylaxis or nonallergic bronchial asthma, bronchial hyperresponsiveness, common cold, acute rhinitis are acute or chronic Bronchitis, influenza, pneumonia, COPD, chronic obstructive bronchitis, pulmonary emphysema, lung cancer, (acute respiration is embarrassed by ARDS Compel syndrome), cystic fibrosis, pulmonary fibrosis, silicosis and sarcoidosis.
  15. 15. the composition containing N- acetyl diaminobutyric acid, the salt of N- acetyl diaminobutyric acid or ester is used for Treatment and/or prevention conjunctivitis are specifically in the method for allergy correlation membranous conjunctivitis.
  16. 16. the composition containing N- acetyl diaminobutyric acid, the salt of N- acetyl diaminobutyric acid or ester is used for Treatment and/or prevention gastrointestinal tract chronic inflammatory disease method in, the gastrointestinal tract chronic inflammatory disease be specifically Crohn disease, Ulcerative colitis or gastritis or intestinal irritable syndrome.
  17. 17. the composition containing N- acetyl diaminobutyric acid, the salt of N- acetyl diaminobutyric acid or ester is used for The inflammation and damage and/or stomach or duodenal ulcer for the treatment of and/or prevention gastroesophageal reflux disease, stomach or duodenal mucosa Method in.
  18. 18. the composition containing N- acetyl diaminobutyric acid, the salt of N- acetyl diaminobutyric acid or ester is used for In the method for restoring impaired bodily tissue.
  19. 19. the composition of purposes according to claim 18, it is characterised in that the damage of the bodily tissue is wound or ulcer, The either result of diabetic foot syndrome.
  20. 20. the composition containing N- acetyl diaminobutyric acid, the salt of N- acetyl diaminobutyric acid or ester is used for It treats in the method for hemorrhoid.
  21. 21. the composition containing N- acetyl diaminobutyric acid, the salt of N- acetyl diaminobutyric acid or ester is used for Ear disease is treated, specifically in the method for otitis externa and pruritus.
  22. 22. according to the composition of the purposes of any one of claim 2 to 21, which is characterized in that the composition contains N- γ- Acetyl group -2,4- diaminobutyric acid and/or N- α-acetyl group -2,4- diaminobutyric acid.
  23. 23. the composition of purposes according to claim 22, it is characterised in that the composition contains N- γ-acetyl group-L-2,4- Diaminobutyric acid and/or N- α-acetyl group-L-2,4- diaminobutyric acid.
  24. 24. the composition for containing N- acetyl diaminobutyric acid, the salt of N- acetyl diaminobutyric acid or ester is used as storing The purposes of the component of the preservation solution of transplant organ, transplant organ system or transplanting tissue.
  25. 25. the cosmetic composition containing N- acetyl diaminobutyric acid, the salt of N- acetyl diaminobutyric acid or ester.
  26. 26. cosmetic treatments pass through the combination containing N- acetyl diaminobutyric acid, the salt of N- acetyl diaminobutyric acid or ester Object carries out skin or mucous membrane.
CN201780087060.3A 2016-12-22 2017-12-22 Composition containing N- acetyl diaminobutyric acid Pending CN110461321A (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE102016125414.2A DE102016125414A1 (en) 2016-12-22 2016-12-22 Composition containing N-acetyldiaminobutyric acid
DE102016125414.2 2016-12-22
PCT/EP2017/084454 WO2018115475A2 (en) 2016-12-22 2017-12-22 N-acetyldiaminobutyric acid-containing composition

Publications (1)

Publication Number Publication Date
CN110461321A true CN110461321A (en) 2019-11-15

Family

ID=62186383

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201780087060.3A Pending CN110461321A (en) 2016-12-22 2017-12-22 Composition containing N- acetyl diaminobutyric acid

Country Status (7)

Country Link
US (1) US20190380985A1 (en)
EP (1) EP3558287A2 (en)
CN (1) CN110461321A (en)
BR (1) BR112019012788A2 (en)
DE (1) DE102016125414A1 (en)
MX (1) MX2019007490A (en)
WO (1) WO2018115475A2 (en)

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU664710B2 (en) * 1991-08-27 1995-11-30 Upjohn Company, The A method for treatment of metabolic disorders
DE10222561B4 (en) 2002-05-17 2009-12-10 Dr. Franz Köhler Chemie GmbH Protective solution for the prevention of ischemic damage
DE10330243A1 (en) 2003-07-03 2005-01-20 bitop Aktiengesellschaft für biotechnische Optimierung Use of osmolytes derived from extremophilic bacteria for the manufacture of medicines for the external treatment of atopic dermatitis
DE102006056766A1 (en) 2006-12-01 2008-06-05 Bitop Ag Use of compatible solutes
WO2010006792A1 (en) 2008-07-16 2010-01-21 Bitop Ag Synthesis of cyclic amidines

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CANOVAS D ET AL: "Role of Nγ-acetyldiaminobutyrate as an enzyme stabilizer and an intermediate in the biosynthesis ofhydroxyectoine", 《APPLIED AND ENVIRONMENTAL MICROBIOLOGY》 *

Also Published As

Publication number Publication date
DE102016125414A1 (en) 2018-06-28
BR112019012788A2 (en) 2019-12-03
MX2019007490A (en) 2019-12-11
WO2018115475A2 (en) 2018-06-28
WO2018115475A3 (en) 2018-08-23
EP3558287A2 (en) 2019-10-30
US20190380985A1 (en) 2019-12-19

Similar Documents

Publication Publication Date Title
US10987333B2 (en) Methods and compositions for preventing and treating auditory dysfunctions
ES2368974T3 (en) PREPARATION CONTAINING OSMOLITES FOR USE IN CASE OF DRY MUCOUS MEMBRANES.
CN103200952B (en) The treatment of disease
ES2800915T3 (en) Composition containing glucosylglycerol to promote the regeneration of injured body tissues
JP2019501108A (en) Mussel adhesion protein product and use thereof for inhibiting mucosal inflammation
CN107050036A (en) The treatment method of disease
EP3383395A1 (en) Compatible solute or solute mixture for use in the prevention or treatment of diseases having barrier defects in epithelial tissues
Liu et al. Mainstream cigarette smoke induces autophagy and promotes apoptosis in oral mucosal epithelial cells
KR102006950B1 (en) Cosmetics compositions for hair growth promoter
ES2927928T3 (en) Use of an antimicrobial composition
CN110461321A (en) Composition containing N- acetyl diaminobutyric acid
KR20220079860A (en) new peptide
WO2013133062A1 (en) Coating agent for allergic rhinitis
ITRM20130657A1 (en) TREATMENT OF DERMATOPATHIES BY VEGETAL EXTRACT BY DAPHNE LAUREOLA
US20160243080A1 (en) Formulations of angiotensin receptor blockers
WO2010005770A2 (en) Electrostatically charged nasal application multipurpose products and method
CN109563150A (en) By the treatment for the disease that vascular hyperpermeability mediates
JPH0219323A (en) Use of lysozyme in production of nasal viscous membrane protective agent
Hou et al. Enhanced transdermal lymphatic drug delivery of hyaluronic acid modified transfersome for tumor metastasis therapy
RU2770517C1 (en) Agent based on a liposomal form of a photosensitizer and a method for its preparation for the prevention and treatment of infectious and inflammatory diseases of the oral cavity, nasopharynx and upper respiratory tract
CN116350746B (en) Application of sardine peptide composition in medicines for treating allergic rhinitis
RU2212235C1 (en) Nasal drop &#34;brizolin&#34; eliciting vasoconstrictive, anti-inflammatory and antiedematous effect
KR20220119051A (en) Novel multifunctional oligopeptides
CN114929726A (en) Novel peptides and their use in the treatment of inflammation
WO2019190503A1 (en) Methods and compositions for treating parkinson&#39;s disease

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
WD01 Invention patent application deemed withdrawn after publication

Application publication date: 20191115

WD01 Invention patent application deemed withdrawn after publication